Do All Fractures Need Surgery?

Common fractures managed by orthopaedic surgeons include ankle fractures, proximal humerus fractures in patients older than 60 years, humeral shaft fractures, and distal radius fractures. Recent trends indicate that surgical management is the best option for most fractures. However, there is limited evidence regarding whether most of these fractures need surgery, or whether there is a subset that could be managed without surgery, with no change in outcomes, or even possibly having improved results with lower complication rates with nonsurgical care.

Biomimetic Targeting of Nanoparticles to Immune Cell Subsets via Cognate Antigen Interactions.

Within the body, cellular recognition is mediated in large part by receptor-ligand interactions that result from the surface marker expression of the participant cells. In the case of immune cells, these interactions can be highly specific, enabling them to carry out their protective functions in fighting off infection and malignancy. In this work, we demonstrate the biomimetic targeting of antigen-specific immune cell populations by using nanoparticles functionalized with natural membrane derived from cells expressing the cognate antigen. Using red blood cell (RBC)-specific B cells as a model target, it is shown that RBC membrane-coated nanoparticles exhibit enhanced affinity compared with control nanoparticles. The concept is further demonstrated using murine models of alloimmunity and autoimmunity, where B cells elicited against RBCs can be positively labeled using the biomimetic nanoparticles. This strategy for antigen-specific immune cell targeting may have utility for the detection and treatment of various autoimmune conditions, and it may additionally have implications for the prevention of immune cell malignancies.

Clearance of pathological antibodies using biomimetic nanoparticles.

Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs.

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery.

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.

Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery.

Cell-derived nanoparticles have been garnering increased attention due to their ability to mimic many of the natural properties displayed by their source cells. This top-down engineering approach can be applied toward the development of novel therapeutic strategies owing to the unique interactions enabled through the retention of complex antigenic information. Herein, we report on the biological functionalization of polymeric nanoparticles with a layer of membrane coating derived from cancer cells. The resulting core-shell nanostructures, which carry the full array of cancer cell membrane antigens, offer a robust platform with applicability toward multiple modes of anticancer therapy. We demonstrate that by coupling the particles with an immunological adjuvant, the resulting formulation can be used to promote a tumor-specific immune response for use in vaccine applications. Moreover, we show that by taking advantage of the inherent homotypic binding phenomenon frequently observed among tumor cells the membrane functionalization allows for a unique cancer targeting strategy that can be utilized for drug delivery applications.

The Relationship Between Height and Income With Potential Application to Treatment of Limb Length Discrepancy.

Purpose When treating limb length discrepancy (LLD), decisions regarding lengthening versus contralateral shortening require careful consideration of deformity and patient factors. Using the National Longitudinal Survey of Youth 1979 (NLSY79) database, and income as a quantitative representation of overall socioeconomic benefit, we sought to determine the height at which incremental gains in height have the greatest value. Methods Using the NLSY79 database, we collected demographic data, height, yearly income from wages, college education (full- or part-time), and receipt of government financial aid. Multiple-linear regression and graphical analysis were performed. Results The study population included 9,652 individuals, 4,775 (49.5%) males and 4,877 (50.5%) females. Mean heights were 70.0±3.0 inches and 64.3±2.6 inches for males and females, respectively. Multiple-linear regression analysis (adjusted-r²=0.33) demonstrated height had a standardized-ß=0.097 (p<0.001), even when accounting for confounding factors. Using graphical analysis, we estimated cut-offs of 74 inches for males and 69 inches for females, beyond which income decreased with incremental height. Conclusions Using income as a quantitative representation of socioeconomic value, our analysis found income increased with incremental height in individuals with predicted heights up to 74 inches for males and 69 inches for females. Shortening procedures might receive more consideration at predicted heights greater than these cut-offs, while lengthening might be more strongly considered at the lower ranges of height. Additionally, our multiple-linear regression analysis confirms the correlation between height and income, when factoring in other predictors of income.

Are Readmissions After Total Knee Arthroplasty Preventable?

Readmission within 90 days following total joint arthroplasty has become a central quality measure of reimbursement initiatives; however, the validity of readmission rates as a measure of hospital care quality and the proportion of readmissions that are preventable are unknown. The purpose of this study is to determine if readmissions within 30 and 90 days after total knee arthroplasty (TKA) were related to orthopaedic or medical etiology and identify if these readmissions were preventable. We retrospectively reviewed 1,625 elective TKAs performed between 2011 and 2014 at our institution. Readmissions within 30 and 90 days were categorized into orthopaedic and medical etiologies and an expert research panel determined if readmissions were potentially preventable based on objective criteria from national or peer-reviewed consensus guidelines. Out of the 1,625 TKAs performed during the study period, there were a total of 79 (4.8%) readmissions within 90 days of surgery, of which 17 (22%) were of orthopaedic etiology and 62 (78%) were of medical etiology. Fifty-two (66%) of the 79 readmissions occurred within 30 days, with 11 (21%) of orthopaedic and 41 (80%) of medical etiology. Only 2 of 79 (3%) readmissions within 90 days were deemed potentially preventable, and neither of them were orthopaedic in nature. Hospital readmissions after total joint arthroplasty are inevitable; however, only a small percentage (3%) of readmissions to our health care system was potentially preventable. Orthopaedic readmissions constituted a minority of the proportion of readmissions at 30 or 90 days, and none were deemed preventable.

Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds.

Metastatic disease remains the primary cause of mortality in cancer patients. Yet the number of available in vitro models to study metastasis is limited by challenges in the recapitulation of the metastatic microenvironment in vitro, and by difficulties in maintaining colonized-tissue specificity in the expansion and maintenance of metastatic cells. Here, we show that decellularized scaffolds that retain tissue-specific extracellular-matrix components and bound signalling molecules enable, when seeded with colorectal cancer cells, the spontaneous formation of three-dimensional cell colonies that histologically, molecularly and phenotypically resemble in vivo metastases. Lung and liver metastases obtained by culturing colorectal cancer cells on, respectively, lung and liver decellularized scaffolds retained their tissue-specific tropism when injected in mice. We also found that the engineered metastases contained signet ring cells, which has not previously been observed ex vivo. A culture system with tissue-specific decellularized scaffolds represents a simple and powerful approach for the study of organ-specific cancer metastases.

Safe and Immunocompatible Nanocarriers Cloaked in RBC Membranes for Drug Delivery to Treat Solid Tumors.

The therapeutic potential of nanoparticle-based drug carriers depends largely on their ability to evade the host immune system while delivering their cargo safely to the site of action. Of particular interest are simple strategies for the functionalization of nanoparticle surfaces that are both inherently safe and can also bestow immunoevasive properties, allowing for extended blood circulation times. Here, we evaluated a recently reported cell membrane-coated nanoparticle platform as a drug delivery vehicle for the treatment of a murine model of lymphoma. These biomimetic nanoparticles, consisting of a biodegradable polymeric material cloaked with natural red blood cell membrane, were shown to efficiently deliver a model chemotherapeutic, doxorubicin, to solid tumor sites for significantly increased tumor growth inhibition compared with conventional free drug treatment. Importantly, the nanoparticles also showed excellent immunocompatibility as well as an advantageous safety profile compared with the free drug, making them attractive for potential translation. This study demonstrates the promise of using a biomembrane-coating approach as the basis for the design of functional, safe, and immunocompatible nanocarriers for cancer drug delivery.

Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis.

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ((90)Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

Folate-targeted polymeric nanoparticle formulation of docetaxel is an effective molecularly targeted radiosensitizer with efficacy dependent on the timing of radiotherapy.

Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72 ± 4 nm and surface charges of -42 ± 8 mV. Using folate receptor overexpressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 h) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and nontargeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor overexpressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers.